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Methods

We use a single-blinded intervention with two parallel groups (a learning therapy
group and a waiting list control group). Testers are blind to the study hypothesis
and the group membership of participants. Through an advertisement in local newspaper,
64 healthy older adults are recruited. They will be assigned randomly to a learning
therapy group or a waiting list control group. In the learning therapy group, participants
are required to perform two cognitive tasks for 6 months: reading Japanese aloud and
solving simple calculations. The waiting list group does not participate in the intervention.
The primary outcome measure is the Stroop test score: a measure of executive function.
Secondary outcome measures are assessments including the following: verbal fluency
task, logical memory, first and second names, digit span forward, digit span backward,
Japanese reading test, digit cancellation task, digit symbol coding, and symbol search.
We assess these outcome measures before and after the intervention.

Discussion

This report is the first study which investigates the beneficial effects of learning
therapy on a wide range of cognitive functions of elderly people. Our study provides
sufficient evidence of learning therapy effectiveness. Most cognitive functions, which
are correlated strongly with daily life activities, decrease with age. These study
results can elucidate effects of cognitive training on elderly people.

Trial registration

This trial was registered in The University Hospital Medical Information Network Clinical
Trials Registry (No. UMIN000006998).

Although human cognitive function typically declines with age, earlier studies showed
that several cognitive training programs can improve cognitive functions such as memory
[18,26], processing speed [21,27,28], executive function [29,30], and attention [31] in healthy elderly people. It is particularly interesting that some studies have
demonstrated that the effects of cognitive training can impact non-trained cognitive
functions or tasks [30,32-35]. For instance, Schmiedek [35] conducted a working memory training study for elderly people in which participants
were required to perform auditory recognition, discrimination, and memory tasks for
about 15 min per day at least 5 days per week, for 8 to 10 weeks. Elderly people in
the training group showed improvement of cognitive function in directly trained tasks
(for example, alpha span and word list) and in cognitive functions in non-trained
tasks (for example, animal span, rotation span, word pairs). Results of earlier studies
show that cognitive training (for example working memory training) can improve cognitive
functions in elderly people.

In line with previous studies using cognitive training for elderly people, we recently
developed a new mode of cognitive training using reading aloud and solving of simple
arithmetic calculations, namely learning therapy [30,36]. Learning therapy is designed for stimulation of the frontal cortex (especially dorsolateral
prefrontal cortex) and of the temporal and parietal association cortices by cognitive
tasks, thereby engendering improvement of the function of these cortices [36]. We specifically targeted these regions for the following reasons: (1) Previous functional
magnetic resonance imaging (MRI) studies showed that task-related activation of these
regions in older adults is lower than that in younger adults [37-42]; (2) Previous structural MRI studies using voxel-based morphometry (VBM) showed that
regional gray and white matter volumes of these regions decline with age [43-45]; and (3) These activity and regional gray matter volumes of these regions are closely
linked to cognitive functions [39,46-52] such as executive functions, processing speed, and memory, which decrease with age.
Therefore, cognitive decline in elderly people might result from reductions of activities
and volume in these regions. Based on these facts, we assumed that stimulation of
the frontal cortex (especially the dorsolateral prefrontal cortex), as well as those
of the temporal and parietal association cortices by cognitive tasks might improve
activities and regional gray matter volumes of these cortices. Moreover, they might
engender improvement of the functions of these cortices [10,11,18,36,53].

Learning therapy used two simple and easy training tasks (reading Japanese aloud and
solving simple arithmetic calculations) derived from knowledge of neuroscience. Results
of brain imaging studies indicate that reading sentences or words aloud [54-58] and simple arithmetic operations [59-61] activate the three associated cortices, especially the prefrontal cortex. Reading
aloud is accomplished using a combination of several cognitive processes such as recognition
of visually presented words, conversion to phonological representation from graphic
representation of words, analysis of the meaning of words, and control of pronunciation.
Solving arithmetic problems is also accomplished through the use of numerous cognitive
processes such as recognition of visually presented numbers, arithmetic operations,
and control of hand movements. Moreover, the bilateral prefrontal cortices are activated
even when solving very simple and easy problems. Both reading aloud and solving arithmetic
problems require working memory. This prefrontal stimulation might engender the positive
transfer effect on other cognitive functions. Learning therapy has outstanding features
compared to previous cognitive training. First, training tasks of learning therapy
are based on results of neuroscience. Secondly, the training tasks are extremely simple
and easy for elderly people to perform. Consequently, elderly people can readily comprehend
and perform training tasks.

Previous studies using learning therapy have demonstrated that learning therapy can
improve executive functions and processing speed in healthy elderly people. For instance,
Uchida and Kawashima [30] conducted a randomized controlled trial using learning therapy for healthy elderly
people. Participants were divided into learning therapy and control groups. The learning
therapy group was required to do two training tasks for 5 days a week: reading Japanese
aloud and conducting simple calculations. After 6 months, the learning therapy group
showed improved scores in the frontal assessment battery (FAB at bedside), which measures
executive function [62-64], and a digit-symbol substitution test, which measures processing speed [65]. These results suggest that learning therapy beneficially affects some cognitive
functions in elderly people.

Purpose of this study

An earlier study showed effects of learning therapy transferred to executive functions
and processing speed [30]. However, it remains unclear whether or not the effects of learning therapy can transfer
(improve) other cognitive functions such as memory and attention in elderly people.
Consequently, the purpose of this study is to investigate whether or not learning
therapy can transfer to a wide range of cognitive functions in elderly people. To
reveal transfer effects of learning therapy on cognitive functions, we conduct a single-blinded
randomized control trial using learning therapy. Testers are blinded to the study
hypothesis and the group membership of participants. To evaluate the transfer effects
of the reading aloud and solving simple arithmetic calculations interventions (learning
therapy), we assess a broad range of cognitive functions. The measured cognitive functions
are divisible into seven categories: executive functions, episodic memory, short-term
memory, working memory, reading ability, attention, and processing speed.

Method

Randomized controlled trial design and setting of this trial

This study, which was registered in the University Hospital Medical Information Network
(UMIN) Clinical Trial Registry (UMIN000006998), is a randomized controlled trial conducted
in Sendai city, Miyagi prefecture, Japan. Written informed consent to participate
in the study will be obtained from each participant before enrolment. The protocol
of this study and informed consent were approved by the Ethics Committee of the Tohoku
University Graduate School of Medicine.

To assess the impact of learning therapy on a wide range of cognitive functions in
healthy elderly people, we use a single-blinded intervention with two parallel groups:
a learning therapy group and a waiting list control group. Testers are blind to the
study's hypothesis and the group membership of participants. The Consolidated Standards
of Reporting Trials (CONSORT) statement [66]http://www.consort-statement.org/home/webcite has been used as a framework for developing the study methodology (Additional file
1). The trial design is shown in Figure 1.

Additional file 1.CONSORT 2010 checklist of information to include when reporting a randomized trial*.

Recruitment and selection of participants

Participants are recruited from the general population through advertisements in the
local town paper and local newspaper. Interested participants are screened using a
semi-structured telephone interview. After the telephone interview, participants are
invited to visit Tohoku University for a more detailed screening assessment and to
provide written informed consent.

Inclusion and exclusion criteria

The purpose of this intervention is to investigate transfer effects of learning therapy
for a range of cognitive functions in healthy older adults. The criteria include participants
who report themselves to be right-handed, native Japanese speakers, unconcerned about
their own memory functions, not using medications known to interfere with cognitive
functions (including benzodiazepines, antidepressants or other central nervous agents),
and having no disease known to affect the central nervous system, including thyroid
disease, multiple sclerosis, Parkinson disease, stroke, severe hypertension (systolic
blood pressure is over 180, diastolic blood pressure is over 110), and diabetes. Age
of participants is over 65 years old. Criteria exclude participants who have an Intelligence
Quotient (IQ) less than 85 derived from Japanese Reading Test (JART) [67]. Participants who will participate in another cognitive-related intervention studies
will be excluded.

Randomization

Randomization is designed to take place after receiving the informed consent statement.
A researcher (RN) with no contact with the study participants randomly assigns participants
to either the learning therapy or the waiting list group by random draw using an online
computer program http://www.graphpad.com/quickcalcs/index.cfmwebcite. Letters are used to inform participants of their allocation.

Learning therapy group (cognitive intervention group)

The cognitive intervention method is the same as that used in our previous study using
learning therapy for healthy older adults [30]. Training tasks use two simple tasks (solving arithmetic and Japanese language problems)
that are systematized basic problems in arithmetic and reading [30,36]. We prepared various materials used in everyday classes of first-grade to fourth-grade
elementary school students. The problems are printed on both sides of an A4 sheet
of paper (210 × 297 mm). For the arithmetic problems, the lowest level of difficulty
is single-digit addition. The highest level is three-digit division. For the Japanese
language problems, the lowest level of difficulty is reading and writing simple sentences.
The highest level is reading fairy tales aloud.

One or two weeks before the start of the intervention program, intervention group
participants are asked to go to a classroom. The appropriate level of difficulty and
workload for all participants is assessed by diagnostic tests, which consist of 70
arithmetic and 16 language problems. The arithmetic problems range in difficulty from
single-digit addition to three-digit division. The language problems range in difficulty
from reading and comprehending Japanese Haiku (17 characters) to reading and comprehending stories (110 characters). For tests of
both types, the percentage of correct answers and the time it takes to solve all problems
are determined. In this intervention, the difficulty level and workload of each task
are set such that each participant is able to solve the problems with ease and without
mental stress within 15 min.

The cognitive intervention is scheduled to be conducted for 23 weeks. Participants
in the cognitive intervention group are asked to go to the classroom in Tohoku University
once a week. They are instructed to complete five sheets of each task prepared for
each for that day, which are assessed by staff members. Mistakes are corrected by
the participants themselves. The study period ends when the participants complete
each of the problems correctly. The daily learning time for the two tasks is approximately
15 min. The cognitive intervention is undertaken on an individual basis, so that the
participants can decide how to use their learning time of 15 min freely. Participants
are also asked to do their homework of two tasks for 4 to 6 days a week. Regarding
their homework, participants are asked to complete five sheets of each task prepared
for each. Furthermore, participants are asked to bring back their achievements of
homework on the next school day. The staff members check their homework and provide
advice when necessary.

Waiting list group (no cognitive intervention group)

The wait-listed group receives no intervention. Those participants are informed by
letter that they are scheduled to receive an invitation to participate after a waiting
period of 6 months. No placebo is used for the social contact group. Results of previous
intervention studies [26,68] report that a placebo group is unnecessary for this type of study because no difference
exists in cognitive or functional improvement between the placebo and no-social-contact
groups (control group).

Overview of cognitive function measures

To evaluate the beneficial effects of learning therapy on cognitive functions, we
assess a broad range of cognitive functions (Table 1). Measures of the cognitive functions are divisible into seven categories (executive
functions, episodic memory, short-term memory, working memory, reading ability, attention,
and processing speed). Executive functions are measured using the Stroop test (ST)
[69] and verbal fluency task (VFT) [70]. Episodic memory is measured using logical memory (LM) [71] and first and second names (FS-N) [72]. Short-term memory is measured using digit span forward (DS-F) [65]. Working memory is measured using digit span backward (DS-B) [65]. Reading ability is measured using the Japanese reading test (JART) [67]. Attention is measured using the digit cancellation task (D-CAT) [73]. Processing speed is measured using digit symbol coding (Cd) [65] and symbol search (SS) [65]. Details of all tasks are described below.

We assess these cognitive function measures before and after the intervention period
(6 months). The primary outcome measure is ST. We selected ST as the primary outcome
measure because: (1) learning therapy is expected to improve executive functions,
and a previous study showed learning therapy can improve executive function measured
by FAB [30]; (2) ST is a task that is often used to measure executive functions [74,75]; and (3) ST has been standardized, with high reliability and validity in Japanese
populations [69,76].

ST

Stroop test (ST) measures executive function including response inhibition and impulsivity.
Hakoda's version is a paper and pencil version ST [69]. In this test, participants must check whether their chosen answers are correct,
unlike the traditional oral naming ST. We use a reverse ST and a ST. In the reverse
ST, in the leftmost of six columns, a word naming a color is printed in another color
(for example 'red' is printed in blue letters); the other five columns are each filled
with five different colors from which participants must check the column whose color
matches the written word in the leftmost column. In the ST, in the leftmost of six
columns, a word naming a color is printed in another color (for example 'red' is printed
in blue letters) and the other five columns contain words naming colours. Participants
must check the column containing the word naming the color of the word in the leftmost
column. In each task, participants are instructed to complete as many of these exercises
as possible in 1 min. The primary measure for this task is the number of correct items.

VFT

Verbal fluency task (VFT) measures executive function. We use the Japanese version
of VFT [70], which has two tasks (letter fluency task (LFT) and category fluency (CFT) task).
In LFT, a Japanese letter, 'ka', is given to each participant, who is then asked to
generate common nouns beginning with this letter - as many as possible in 60 s. In
CFT, a category name (animal) is given to each participant, who is then asked to generate
many words of a certain category (animal). The participants are instructed not to
include proper nouns or to repeat one that has already been stated. The primary measure
for this task is the number of words reported. The reliability and validity of Japanese
LFT were demonstrated by Ito [70].

LM

Logical memory (LM) evaluates the performance of episodic memory. LM is a subtest
of the Wechsler Memory Scale-Revised (WMS-R) [71]. LM consists of two short paragraph-length stories (Story A and Story B). In LM,
participants must memorize the short story. The stories are scored in terms of the
number of story units recalled, as specified in the WMS-R scoring protocol. We use
either Story A or Story B. The primary measure for this task is the number of correct
story units recalled.

FSN

First and second names (FSN) evaluates memory ability in everyday life. FSN is a subset
of Rivermead Behavioral Memory Test (RBMT) [72]. RBMT measures episodic memory as it is used in everyday life. Therefore, subsets
of RBMT are similar to everyday situations. In FSN, participants must memorize first
and second names with faces (photograph). Subsequently, they must recall the first
and the second names when the face is shown again later. We use four faces (four first
names and four second names). The primary measure of this test is the total number
of correct answers in both first and second names. The maximum raw score of FSN is
8.

DS

Digit span (DS) is a subtest in Wechsler Adult Intelligence Scale-Third Edition (WAIS-III)
[65]. DS, which has two subsections (DS-F and DS-B), evaluates short-term memory and working
memory. DS-F measures short-term memory by simply requiring participants to repeat
numbers. DS-B measures working memory by requiring participants to memorize numbers
and repeat the numbers in the inverse order. For DS-F, participants repeat numbers
in the same order as they were read aloud by the examiner. For DS-B, participants
repeat numbers in the reverse order of that presented aloud by the examiner. In both,
the examiner reads a series of number sequences which the examinee must repeat in
either forward or reverse order. DS-F has 16 sequences. DS-B has 14 sequences. The
primary measures of this test are raw scores that reflect the number of correctly
repeated sequences until the discontinue criterion (that is, failure to reproduce
two sequences of equal length) is met [65]. The maximum raw score of DS-F is 16. The maximum raw score of DS-B is 14.

JART

The Japanese reading test (JART) measures reading ability [67]. JART is a Japanese version of the National Adult Reading Test (NART) which has a
reading test of 50 irregularly spelled words in English (for example ache) [77]. JART is a reading test comprising 25 Kanji compound words (e.g. 親父, 煙草). The reading
stimuli are printed out randomly for reading. The participants are asked to read each
Kanji compound word aloud. This task assesses reading ability and IQ. The primary
measure for this task is the number of correct items.

D-CAT

Digit cancellation task (D-CAT) evaluates attention [73]. The test sheet consists of 12 rows of 50 digits. Each row contains five sets of
numbers 0 to 9 arranged in random order. Consequently, any one digit appears five
times in each row with randomly determined neighbours. D-CAT consists of three such
sheets. Participants are instructed to search for the target number(s) that had been
specified to them and to delete each one with a slash mark as quickly and as accurately
as possible until the experimenter sends a stop signal. There are three trials, first
with a single target number (6), second with two target numbers (9 and 4), and third
with three (8, 3, and 7). Each trial is given for 1 min. Consequently, the total time
required for D-CAT is 3 min. In the second and third trials, it is emphasized that
all the target numbers instructed should be cancelled without omission. The primary
measure of this test is the number of hits (correct answers). We use only the number
of hits in the first trial.

Cd

Digit symbol coding (Cd) is a subtest of WAIS-III [65]. This test measures processing speed. For Cd, the participants are shown a series
of symbols that are paired with numbers. Using a key within a 120 s time limit, participants
draw each symbol under its corresponding number. The primary measure of this test
is the number of correct answers.

SS

Symbol search (SS), a subtest of WAIS-III containing 60 items [65], measures processing speed. For this subtest, participants visually scan two groups
of symbols (a target group and a search group) and report whether either of the target
symbols matches any symbol in the search group. Participants respond to as many items
as possible within a 120 s time limit. The primary measure of this test is the number
of correct answers.

Sample size

Our sample size estimation is based on the change score in the reverse ST, which is
the primary outcome in this study. We expected to detect a large effect size (η2 = 0.14) of the change score in the reverse ST between learning therapy and waiting
list groups. the sample size was determined using G * power [78,79] based on 80% power, a two-sided hypothesis test, an alpha level of 5%, an analysis
of covariance (ANCOVA) model that includes a baseline reverse Stroop task score, age,
and sex as a covariate. The sample size calculation indicated that we need 32 participants
in each of the learning therapy and waiting list groups with consideration of a 20%
drop-out rate.

Analysis

This study is designed to evaluate the beneficial effect of learning therapy in elderly
people. We calculate the change score (post-training score minus pre-training score)
in all cognitive function measures. We conduct an ANCOVA for the change scores in
each cognitive test. The change scores are the dependent variable. Groups (learning
therapy, waiting list) are the independent variable. Pre-training scores in the dependent
variable, sex, age categories are the covariates to exclude the possibility that any
pre-existing difference of measure between groups affect the result of each measure
and to adjust for background characteristics. The level of significance is set at
p < 0.05. Moreover, we report eta squared (η2) as an index of effect size. It is the standardized difference in the change score
between intervention groups (learning therapy group, waiting list group). In actuality,
η2 ≥ 0.01 is regarded as a small effect, η2 ≥ .006 as a medium effect, and η2 ≥ 0.14 as a large effect [80]. Missing data are imputed using the expectation-maximization method, as implemented
in the Statistical Package for the Social Sciences (SPSS) Missing Value Analysis.
It imputes missing values using maximum likelihood estimation with the observed data
in an iterative process [81]. All randomized participants are included in the analyses in line with their allocation,
irrespective of how many sessions they complete (intention-to-treat principle). All
analyses are performed using SPSS software (ver. 18 or higher).

Discussion

This study is designed to investigate the beneficial effects of learning therapy on
widely various cognitive functions such as executive functions, episodic memory, short-term
memory, working memory, reading ability, attention, and processing speed in healthy
elderly people.

This study has several strengths compared to earlier studies using cognitive training
for elderly people. First, this study was designed according to CONSORT guidelines
[66]http://www.consort-statement.org/consort-statement/webcite, which are intended to improve standards of reporting of randomized clinical trials
(RCT). Consequently, this study has been structured to enable its reproduction in
both research and clinical settings. Moreover, we can provide sufficient evidence
of the effectiveness of cognitive training such as learning therapy.

Second, we investigate the beneficial effects of learning therapy on widely various
cognitive functions. The measures assess cognitive functions of seven categories:
executive functions, episodic memory, short-term memory, working memory, reading ability,
attention, and processing speed. Various cognitive functions are necessary to support
our actions and behaviours in everyday life. For instance, when we cook meals, we
must: (1) choose a menu (executive functions); (2) remember the refrigerator contents
(memory); (3) seek and select seasonings from storage (attention); and (4) cut and
prepare cooking ingredients with speed and efficiency (processing speed). Because
of the complexity of such an apparently simple task, it is expected to be important
to investigate the beneficial effects of learning therapy on widely various cognitive
functions.

Third, we use simple, easily learned training tasks (reading aloud and simple calculation)
using paper and pencil. Most training tasks in previous studies were complex tasks
using computers [18,31,82-84]. Using computers might make it easy to record data precisely and to control tasks.
Nevertheless, elderly people often have difficulty using computers [85-87]. The difficulty using computers might cause frustration and other negative emotion,
possibly reducing their motivation to continue. Our training tasks are more familiar
to elderly people and thus expected to encourage their willingness.

This study has some limitations. A first limitation is the intervention period. Our
intervention period is about 6 months. Some previous studies have shown that short-term
intervention (four example 4 to 6 weeks) improved cognitive function in elderly people
[18,20]. Considering reduced costs for elderly people, shorter intervention studies using
learning therapy would be also needed. A second limitation is participants. We recruit
only healthy elderly people for participation in this study. Providing the validity
of effects of learning therapy on widely various cognitive functions, we must conduct
the same randomized controlled trial (RCT) for non-healthy elderly people such as
those with dementia or depression.

In summary, this study is the first to reveal the beneficial effects of learning therapy
on a wide range of cognitive functions in elderly people. Our study is designed to
provide sufficient evidence of effectiveness of learning therapy. Given that most
cognitive functions decrease with age [1] and that these functions are strongly correlated with daily life activities [7-9], our results can elucidate the effects of cognitive training for elderly people.

Trial status

Recruitment of participants begins in February 2012, and is expected to end in January
2013.

Competing interests

Learning therapy was developed by RK and KUMON Institute of Education. However, RK
derives no income from KUMON Institute of Education and Society for Learning Therapy.
RK has no other competing interests. All other authors have declared no competing
interests.

Authors' contributions

RN designed, developed the study protocol, and calculated the sample size. RN and
HN searched the literature, selected cognitive function measures, created manuals
to conduct and rate cognitive measures, and recruited testers for cognitive function
measures. HN conducts cognitive function measures and rates these cognitive function
measures with testers. RN supervises testers. RN wrote the manuscript with YT, HT,
HH, YN, AS, HN, and RK. RK also gave advice related to the study protocol. All authors
read and approved the final manuscript.

Acknowledgements

Ethical approval was provided by the Institutional Review Board of the Tohoku University
Graduate School of Medicine (ref. 2011-153). Based on the Declaration of Helsinki,
written informed consent will be received from each participant. This study is one
industry-academy collaboration of Tohoku University, namely Smart Aging Square http://www2.idac.tohoku.ac.jp/dep/sairc/square.html. This study is supported by the KUMON Institute of Education and a Grant-in-Aid from
the Japan Society for the Promotion of Science (JSPS) for Fellows (grant no. 235019;
http://www.jsps.go.jp/english/e-pd/index.html). Funding sources of the trial have no involvement in the study design, collection,
analysis, interpretation of data, or writing of papers. We thank A. Kasagi for recruiting
the participants, testers for performing psychological tests, supporters for conducting
learning therapy, the participants, and all our other colleagues in IDAC, Tohoku University
for their support.